Open Access

Associations between renal impairment and anemia in older, rural Japanese men: the Nagasaki Island study

  • Yuji Shimizu1Email author,
  • Shimpei Sato1,
  • Jun Koyamatsu2,
  • Hirotomo Yamanashi2,
  • Mako Nagayoshi1,
  • Koichiro Kadota1,
  • Mami Tamai3,
  • Kazuhiko Arima4,
  • Hironori Yamasaki5,
  • Yosuke Kusano6,
  • Noboru Takamura7 and
  • Takahiro Maeda1, 2
Journal of Physiological AnthropologyAn official journal of the Japan Society of Physiological Anthropology (JSPA)201433:7

DOI: 10.1186/1880-6805-33-7

Received: 13 December 2013

Accepted: 2 April 2014

Published: 17 April 2014

Abstract

Background

Renal impairment is known to be associated with atherosclerosis, which in turn is reported to be positively associated with hemoglobin levels. In addition, renal impairment is known to be associated with a form of anemia known as renal anemia.

Methods

To clarify the associations between renal impairment and anemia, we conducted a cross-sectional study of 1,105 60 to 89-year-old men, who were not taking medication for anemia and were undergoing general health check-ups.

Results

Compared with non-chronic kidney disease, chronic kidney disease (CKD) with a glomerular filtration rate (GFR) <60 mL/min/1.73 m2 was found to constitute a significant risk of anemia. However, we noted that this risk was lower for mild renal impairment (60 mL/min/1.73 m2 ≤ GFR <90 mL/min/1.73 m2). Compared with the non-CKD reference group, the classical cardiovascular risk factors adjusted odds ratio (OR) for anemia was 1.81 (1.23 to 2.68) and compared with the normal renal function (GFR ≥90 mL/min/1.73 m2) reference group, the ORs for mild renal impairment and CKD were 0.26 (0.15 to 0.47) and 0.60 (0.33 to 1.09).

Conclusions

Independent from classical cardiovascular risk factors, CKD, which was identified during general health check-ups, appeared to constitute a significant risk of anemia for older Japanese men. For mild renal impairment, however, this association was a reduced risk of anemia and thus possibly a higher risk of atherosclerosis.

Keywords

GFR Anemia Renal impairments CKD Men

Introduction

A decline in the glomerular filtration rate (GFR) was identified as a marker of chronic kidney disease (CKD) that is known to be associated with a form of anemia known as renal anemia.

In a previous study of ours, positive associations were detected between hemoglobin levels and increased arterial stiffness assessed with the cardio-ankle index (CAVI) [1]. Since CAVI was identified as an independent factor associated with GFR in the general population [2], renal impairment might also be positively associated with hemoglobin levels.

To investigate this potential association, we conducted a cross-sectional study of older Japanese men who participated in a general health check-up between 2005 and 2012.

Methods

Subjects

The survey population covered 1,175 men aged 60 to 89 years, who were all residents of the western Japan rural community of the Goto Islands and participated in this study between 2005 and 2012. We used data that were obtained the first time the subjects participated in this study. A total of 66 individuals with missing data and 4 individuals who were taking medication for anemia were excluded, leaving 1,105 men for enrollment in this study. The mean age of the study population was 70.2 years (±6.7 SD; range 60 to 89). Written consent forms were available in Japanese to ensure comprehensive understanding of the study objectives, and informed consent was signed by the participants. This study was approved by the Ethics Committee for Use of Humans of Nagasaki University (project registration number 0501120073).

Data collection and laboratory measurements

Systolic blood pressures were recorded at rest. Body weight and height were measured with an automatic body composition analyzer (BF-220; Tanita, Tokyo, Japan) at the same time blood was drawn. Trained interviewers obtained information on smoking status, drinking status, medical history, use of antihypertensive agents, and use of medication for diabetes mellitus. Fasting blood samples were obtained in an EDTA-2 K tube and were used for measuring hemoglobin with the sodium lauryl sulfate (SLS)-hemoglobin method. Serum concentrations of HDL cholesterol, triglycerides (TG), aspartate aminotransferase (AST), γ-glutamyltraspeptidase (γGTP), creatinine, and hemoglobin A1c (HbA1c), were measured with standard laboratory procedures. The glomerular filtration rate (GFR) was estimated by using an established method with three variations recently proposed by a working group of the Japanese Chronic Kidney Disease Initiative [3].

Definition of disease

Anemia for men was defined as 13 g/dL > hemoglobin in accordance with the recommendation by the World Health Organization (WHO) Study Group [4]. Diabetes was defined as HbA1c ≥6.5% (NGSP: National Glycohemoglobin Standardization Program) and/or initiation of glucose-lowering medication or insulin therapy [5]. On the basis of the Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines [6], we defined normal renal function as GFR ≥90 mL/min/1.73 m2, reduced renal function as GFR <90 mL/min/1.73 m2, mild renal impairment as GFR 60 to 89 mL/min/1.73 m2, and CKD as GFR <60 mL/min/1.73 m2.

Statistical analysis

Differences in age-adjusted mean values or prevalence of potential confounding factors in relation to hemoglobin levels were calculated using ANOVA or logistic regression models. Odds ratios (ORs) and 95% confidence intervals (CIs) for anemia associated with renal impairment (both mild renal impairment and CKD) were calculated with the aid of logistic regression models. First, we adjusted only for age. Second, we included other potential confounding factors, that is, smoking status (never a smoker, former smoker, current smoker), alcohol consumption (non-drinker and current light to moderate drinker (1 to 6 times/week), current heavy drinker (every day)), systolic blood pressure (mmHg), antihypertensive medication use (no, yes), body mass index (kg/m2), diabetes (no, yes), history of cardiovascular disease (no, yes), HDL cholesterol (mg/dL), TG (mg/dL), AST (IU/L), and γGTP (IU/L). All statistical analyses were performed with the SAS system for Windows (version 9.3; SAS Inc., Cary, NC, USA). All P values for statistical tests were two-tailed, and values of <0.05 were regarded as statistically significant.

Results

Of the 1,105 men taking part in the general health check-up program, 645 were diagnosed with mild renal impairment and 351 with CKD, while 162 were diagnosed with anemia.

Table 1 lists age-adjusted characteristics for this population in relation to GFR levels.
Table 1

Age-adjusted mean values and percentage in relation to renal function

 

Non-chronic kidney diseased

Chronic kidney diseasec

P

Normal renal functiona

Mild renal impairmentb

Number at risk

109

645

351

 

Age, years

67.7 ± 6.1

69.6 ± 6.5

72.2 ± 6.7

 

Systolic blood pressure, mmHg

143

143

145

0.344

Antihypertensive medication use, %

31.5

34.3

40.6

0.083

Diabetes, %

14.0

12.0

10.7

0.634

History of cardiovascular disease, %

8.8

10.2

17.4

0.003

Body mass index, kg/m2

22.8

23.5

23.9

0.003

Current drinkers, %

56

46.8

51.1

0.126

Current smokers, %

29.1

21.6

15.2

0.004

Serum HDL cholesterol, mg/dL

57

55

52

0.004

Serum triglycerides (TG), mg/dL

116

112

135

<0.001

Serum aspartate aminotransferase (AST), IU/L

27

25

24

0.021

Serum γ-glutamyltraspeptidase (γGTP), IU/L

44

37

46

0.046

Serum creatinine, mg/dL

0.62

0.82

1.18

<0.001

Glomerular filtration rate (GFR), mL/min/1.73 m2

99.6

72.4

49.8

<0.001

aNormal renal function, bmild renal impairment, and cchronic kidney disease were defined as respectively, GFR ≥90 mL/min/1.73 m2, 90 mL/min/1.73 m2 > GFR ≥60 mL/min/1.73 m2, and GFR <60 mL/min/1.73 m2. dNon-chronic kidney disease includes normal renal function and mild renal impairment.

We found that compared with non-CKD, CKD constituted a significant risk factor for anemia (Table 2). However, when we divided the non-CKD group into a normal renal function group (GFR ≥90 mL/min/1.73 m2) and a mild renal impairment group (60 < GFR ≤90 mL/min/1.73 m2), and used the normal renal function group for reference, mild renal impairment was found to be associated with a significantly lower risk of anemia. CKD was not associated with a higher risk of anemia.
Table 2

Odds ratios (OR) and 95% confidence intervals (CI) for anemia in relation to glomerular filtration rate (GFR) levels

 

Non-chronic kidney diseased

Chronic kidney diseasec

P

Normal renal functiona

 

Mild renal impairmentb

Number at risk

109

 

645

351

 

Number of cases (percentage)

26 (23.9)

 

63 (9.8)

73 (20.8)

 

Age-adjusted OR

 

1.00

 

1.54 (1.08 to 2.20)

0.016

 

1.00

 

0.26 (0.16 to 0.45)

052 (0.30 to 0.89)

0.967

Multivariable OR

 

1.00

 

1.81 (1.23 to 2.68)

0.003

 

1.00

 

0.26 (0.15 to 0.47)

0.60 (0.33 to 1.09)

0.644

aNormal renal function, bmild renal impairment, and cchronic kidney disease (CKD) were defined as respectively, GFR ≥90 mL/min/1.73 m2, 90 mL/min/1.73 m2 > GFR ≥60 mL/min/1.73 m2, and GFR <60 mL/min/1.73 m2. dNon-chronic kidney disease includes normal renal function and mild renal impairment. Anemia: hemoglobin in level <13.0 g/dL. Multivariable OR: adjusted further for age, systolic blood pressure, antihypertensive medication use, body mass index, smoking, alcohol intake, diabetes, history of cardiovascular disease, serum HDL cholesterol, serum triglycerides (TG), serum aspartate aminotransferase (AST), and serum γ-glutamyltranspeptidase (γGTP).

Participants with CKD and anemia showed significantly lower GFR whereas their non-CKD counterparts showed significantly higher GFR. The age-adjusted values for GFR were 50.6 mL/min/1.73 m2 for participants with non-anemic CKD and 44.8 mL/min/1.73 m2 for those with anemic CKD (P <0.001). For non-CKD participants, the corresponding values were 75.5 mL/min/1.73 m2 and 84.3 mL/min/1.73 m2 (P <0.001).

As part of our study, we conducted a further investigation of 1,059 men for whom CAVI data were available. We found that both GFR and hemoglobin were significantly associated with atherosclerosis (CAVI ≥9.0). The age-adjusted odds ratios for risk of atherosclerosis of a one standard deviation (SD) increment in GFR (17.3 mL/min/1.73 m2) and in hemoglobin (1.3 g/dL) were 0.82 (0.71 to 0.95, P = 0.007) and 1.31 (1.14 to 1.50, < 0.001), respectively.

Discussion

The major finding of the study presented here was that CKD, which was diagnosed during general health check-ups, seems to represent a significant risk of anemia for older, rural Japanese men. Since this association was the result of the reduced risk of anemia for mild renal impairment, which might be associated with atherosclerosis, this finding may constitute an important tool for clinical practice dealing with renal impairment.

A previous study of ours reported that hemoglobin levels were positively associated with hypertension [7] and with increased arterial stiffness as evaluated by CAVI [1] for non- anemic men.

Findings of our analyses showed that CKD constitutes a significant risk of anemia when compared with non-CKD, even though we also found that, when compared with normal renal function, CKD does not constitute a greater risk of anemia. Moreover, mild renal impairment proved to be associated with a significantly lower risk of anemia. These findings suggest that the positive association between CKD and anemia in comparison with non-CKD is not caused mainly by renal anemia but by the influence of the lower risk of anemia associated with mild renal impairment. Since the target population for our study consisted of healthy older Japanese men, the number of participants with CKD accompanied by anemia was relatively small: 73 with anemic CKD as compared with 278 with non-anemic CKD. However, a previous Japanese study of older men (aged ≥70 years) showed that the odds ratio for risk of anemia was significantly higher for a GFR of less than 90 mL/min/1.73 m2[8]. To clarify these discrepancies, we conducted a further analysis, which revealed that both GFR and hemoglobin were significantly associated with atherosclerosis (CAVI ≥9.0). The findings of this additional analysis also indicate that the association between renal condition and hemoglobin level may depend on the balance between atherosclerosis and renal anemia (Figure 1).
https://static-content.springer.com/image/art%3A10.1186%2F1880-6805-33-7/MediaObjects/40101_2013_Article_63_Fig1_HTML.jpg
Figure 1

Association between renal impairment and anemia.

This study has certain potential limitations, which warrant consideration. One of these is that we could not establish any causal relationships because this study was cross-sectional. Since we consider the positive association between hemoglobin and renal impairment to be caused by active atherosclerosis progression, the atherosclerosis should also be classified into stable and progressive atherosclerosis. This indicates the need for a longitudinal study with a larger number of participants.

Conclusions

In conclusion, CKD appeared to constitute a significant risk of anemia for older, rural Japanese men as determined during general health check-ups. For mild renal impairment, however, this association was the result of a reduction in the risk of anemia and thus possibly a higher risk of atherosclerosis.

Abbreviations

AST: 

Aspartate aminotransferase

CAVI: 

Cardio-ankle index

CI: 

Confidence intervals

CKD: 

Chronic kidney disease

GFR: 

Glomerular filtration rate

HbA1c: 

Hemoglobin A1c

NGSP: 

National Glycohemoglobin Standardization Program

ORs: 

Odds ratios

SLS: 

Sodium lauryl sulfate

TG: 

Triglycerides

WHO: 

World Health Organization

γGTP: 

γ-glutamyltraspeptidase.

Declarations

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 22370090).

Authors’ Affiliations

(1)
Department of Community Medicine, Nagasaki University Graduate School of Biomedical Science
(2)
Department of Island and Community Medicine, Nagasaki University Graduate School of Biomedical Science
(3)
Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Science
(4)
Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences
(5)
Center for Health and Community Medicine, Nagasaki University
(6)
Department of Internal Medicine, Nagasaki National Hospital
(7)
Department of Global Health, Medicine and Welfare, Nagasaki University Graduate School of Biomedical Sciences, Atomic Bomb Disease Institute

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Copyright

© Shimizu et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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